Pharmacokinetics of acridine-4-carboxamide in the rat, with extrapolation to humans

Abstract

The pharmacokinetics of N-[2-(dimethyl-amino)ethyl]acridine-4- carboxamide (AC) were investigated in rats after i.v. administration of 18, 55 and 81 mumol/kg [3H]-AC. The plasma concentration-time profiles of AC (as measured by high-performance liquid chromatography) typically exhibited biphasic elimination kinetics over the 8-h post-administration period. Over this dose range, AC's kinetics were first-order. The mean (+/- SD) model-independent pharmacokinetic parameters were: clearance (Cl), 5.3 +/- 1.1 1 h-1 kg-1; steady-state volume of distribution (Vss), 7.8 +/- 3.0 l/kg; mean residence time (MRT), 1.5 +/- 0.4 h; and terminal elimination half-life (t1/2Z), 2.1 +/- 0.7 h (n = 10). The radioactivity levels (expressed as AC equivalents) in plasma were 1.3 times the AC concentrations recorded at 2 min (the first time point) and remained relatively constant for 1-8 h after AC administration. By 6 h, plasma radioactivity concentrations were 20 times greater than AC levels. Taking into account the species differences in the unbound AC fraction in plasma (mouse, 16.3%; rat, 14.8%; human, 3.4%), allometric equations were developed from rat and mouse pharmacokinetic data that predicted a Cl value of 0.075 (range, 0.05-0.10; 95% confidence limits) 1 h-1 kg-1 and a Vss value of 0.63 (range, 0.2-1.1) l/kg for total drug concentrations in humans.